DNAH 基因的体细胞突变与胃腺癌患者更高的化疗反应率相关。
Somatic mutation of DNAH genes implicated higher chemotherapy response rate in gastric adenocarcinoma patients.
机构信息
Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
出版信息
J Transl Med. 2019 Apr 3;17(1):109. doi: 10.1186/s12967-019-1867-6.
BACKGROUND
The dynein axonemal heavy chain (DNAH) family of genes encode the dynein axonemal heavy chain, which is involved in cell motility. Genomic variations of DNAH family members have been frequently reported in diverse kinds of malignant tumors. In this study, we analyzed the genomic database to evaluate the mutation status of DNAH genes in gastric adenocarcinoma and further identified the significance of mutant DNAH genes as effective molecular biomarkers for predicting chemotherapy response in gastric cancer patients.
METHODS
We analyzed the clinical and genomic data of gastric cancer patients published in The Cancer Genome Atlas (TCGA) project. Data on chemotherapy response, overall survival (OS) and chemotherapy-free survival were retrieved. Then, we verified the results via targeted sequencing of gastric cancer patients with similar clinical characteristics but different chemotherapeutic outcomes.
RESULTS
In total, 132 gastric adenocarcinoma patients undergoing chemotherapy treatment from TCGA were included in our study. Somatic mutations in all 13 members of the DNAH family of genes were associated with different chemotherapy responses. Compared with patients with wild-type DNAH genes (n = 59), a significantly higher proportion of those with mutations in DNAH genes (n = 73) (55.9% vs 80.8%) responded to chemotherapy (P = 0.002). Moreover, DNAH mutations were correlated with significantly better OS (P = 0.027), chemotherapy-free survival (P = 0.027), fluoropyrimidine-free survival (P = 0.048) and platinum-free survival (P = 0.014). DNAH mutation status was an independent risk factor for OS (P = 0.015), chemotherapy-free survival (P = 0.015) and platinum-free survival (P = 0.011). We identified somatic mutations in 27 (42.2%) of the 64 stage III gastric adenocarcinoma patients receiving fluoropyrimidine-based chemotherapy by targeted exon sequencing with strict screening conditions. In our own cohort, a significantly higher proportion of patients (n = 32) with DNAH mutations than patients with wild-type DNAH genes (n = 32) had a good prognosis (OS > 48 months) (70.4% vs 35.1%) (P = 0.005).
CONCLUSIONS
Dynein axonemal heavy chain gene mutations contribute positively to chemotherapy sensitivity in gastric cancer patients.
背景
动力蛋白轴索重链（DNAH）家族的基因编码动力蛋白轴索重链，该蛋白参与细胞运动。DNAH 家族成员的基因组变异在多种恶性肿瘤中经常被报道。在这项研究中，我们分析了基因组数据库，以评估 DNAH 基因在胃腺癌中的突变状态，并进一步确定突变 DNAH 基因作为预测胃癌患者化疗反应的有效分子生物标志物的意义。
方法
我们分析了发表在癌症基因组图谱（TCGA）项目中的胃癌患者的临床和基因组数据。检索了化疗反应、总生存期（OS）和无化疗生存期的数据。然后，我们通过对具有相似临床特征但化疗结果不同的胃癌患者进行靶向测序来验证结果。
结果
总共纳入了来自 TCGA 的 132 名接受化疗治疗的胃腺癌患者。13 个 DNAH 家族基因的所有成员的体细胞突变均与不同的化疗反应相关。与野生型 DNAH 基因（n=59）患者相比，突变型 DNAH 基因（n=73）患者（55.9%比 80.8%）对化疗的反应明显更高（P=0.002）。此外，DNAH 突变与明显更好的 OS（P=0.027）、无化疗生存期（P=0.027）、氟尿嘧啶无生存期（P=0.048）和无铂生存期（P=0.014）相关。DNAH 突变状态是 OS（P=0.015）、无化疗生存期（P=0.015）和无铂生存期（P=0.011）的独立危险因素。我们通过严格筛选条件的靶向外显子测序，在 64 名接受氟尿嘧啶类化疗的 III 期胃腺癌患者中发现了 27 例（42.2%）体细胞突变。在我们自己的队列中，与野生型 DNAH 基因患者相比，突变型 DNAH 基因患者的比例（n=32）具有更好的预后（OS>48 个月）（70.4%比 35.1%）（P=0.005）。
结论
动力蛋白轴索重链基因的突变对胃癌患者的化疗敏感性有积极作用。
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